Atherosclerosis remains the leading cause of death in the US. Furthermore, the risk of atherosclerosis is modifiable in any age group. In spite of risk factor modification, the disease burden has remained high in clinical studies, focusing attention on the need for plaque regression. In spite of the clinical desirability of achieving this need, research into the factors that promote this process has been hampered by the lack of appropriate animal models. To overcome this, we and our collaborators have adapted standard mouse models of atherosclerosis progression to generate novel models of regression by applying surgical or genetic approaches. In 2 models, reversal of hyperlipidemia is rapidly achieved and sustained;in a 3rd, the normally low HDL of the apoE-deficient mouse is selectively restored to wild type levels. In all 3 models, plaques undergo remarkable changes in composition, with rapid depletion of monocyte-derived (M-D) foam cells. By studying cell trafficking in vivo, we have established in one model that this depletion of M-D cells occurs via emigration of the cells to lymph nodes, a process suggestive of dendritic cell (DC) behavior. Furthermore, in laser capture microscope-selected plaque cells, we recently found that the gene expression of CCR7, a chemokine receptor required for DC migration, is induced in the regression environment. Overall, the results suggest that regression requires the acquistion of DC properties by M-D foam cells, which have been typically considered to be macrophages. To extend our studies, we propose: 1) to establish the functional requirement for CCR7 in atherosclerosis regression;2) to determine the molecular mechanisms inducing CCR7 gene expression;3) to determine if M-D cell emigration and CCR7 induction is a general feature of plaque regression or specific to one model, as well as to find other factors and pathways regulating regression;4) to detemine whether the HDL- associated enzyme, PAF-AH, is a regulator of plaque regression because of our published data that it improves DC migration and our finding that its plasma level is significantly elevatdd in 2 regression models. Because of the great similarities between the murine and human geneomes, we hope that by defining the regulation of atherosclerosis regression in mouse models, that factors that are clinically relevant and therapeutically approachable will be identified, and thereby have a major impact on public health.